Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process.

To understand the impact of epigenetics on human misfolding disease, we apply Gaussian-process regression (GPR) based machine learning (ML) (GPR-ML) through variation spatial profiling (VSP). VSP generates population-based matrices describing the spatial covariance (SCV) relationships that link genetic diversity to fitness of the individual in response to histone deacetylases inhibitors (HDACi). Niemann-Pick C1 (NPC1) is a Mendelian disorder caused by >300 variants in the NPC1 gene that disrupt cholesterol homeostasis leading to the rapid onset and progression of neurodegenerative disease. We determine the sequence-to-function-to-structure relationships of the NPC1 polypeptide fold required for membrane trafficking and generation of a tunnel that mediates cholesterol flux in late endosomal/lysosomal (LE/Ly) compartments. HDACi treatment reveals unanticipated epigenomic plasticity in SCV relationships that restore NPC1 functionality. GPR-ML based matrices capture the epigenetic processes impacting information flow through central dogma, providing a framework for quantifying the effect of the environment on the healthspan of the individual

Inhibition of HMG CoA reductase reveals an unexpected role for cholesterol during PGC migration in the mouse

<p>Abstract</p> <p>Background</p> <p>Primordial germ cells (PGCs) are the embryonic precursors of the sperm and eggs. Environmental or genetic defects that alter PGC development can impair fertility or cause formation of germ cell tumors.</p> <p>Results</p> <p>We demonstrate a novel role for cholesterol during germ cell migration in mice. Cholesterol was measured in living tissue dissected from mouse embryos and was found to accumulate within the developing gonads as germ cells migrate to colonize these structures. Cholesterol synthesis was blocked in culture by inhibiting the activity of HMG CoA reductase (HMGCR) resulting in germ cell survival and migration defects. These defects were rescued by co-addition of isoprenoids and cholesterol, but neither compound alone was sufficient. In contrast, loss of the last or penultimate enzyme in cholesterol biosynthesis did not alter PGC numbers or position in vivo. However embryos that lack these enzymes do not exhibit cholesterol defects at the stage at which PGCs are migrating. This demonstrates that during gestation, the cholesterol required for PGC migration can be supplied maternally.</p> <p>Conclusion</p> <p>In the mouse, cholesterol is required for PGC survival and motility. It may act cell-autonomously by regulating clustering of growth factor receptors within PGCs or non cell-autonomously by controlling release of growth factors required for PGC guidance and survival.</p

A human iPSC-derived inducible neuronal model of Niemann-Pick disease, type C1

BACKGROUND: Niemann-Pick disease, type C (NPC) is a childhood-onset, lethal, neurodegenerative disorder caused by autosomal recessive mutations in the genes NPC1 or NPC2 and characterized by impaired cholesterol homeostasis, a lipid essential for cellular function. Cellular cholesterol levels are tightly regulated, and mutations in either NPC1 or NPC2 lead to deficient transport and accumulation of unesterified cholesterol in the late endosome/lysosome compartment, and progressive neurodegeneration in affected individuals. Previous cell-based studies to understand the NPC cellular pathophysiology and screen for therapeutic agents have mainly used patient fibroblasts. However, these do not allow modeling the neurodegenerative aspect of NPC disease, highlighting the need for an in vitro system that permits understanding the cellular mechanisms underlying neuronal loss and identifying appropriate therapies. This study reports the development of a novel human iPSC-derived, inducible neuronal model of Niemann-Pick disease, type C1 (NPC1). RESULTS: We generated a null i3Neuron (inducible × integrated × isogenic) (NPC1 CONCLUSION: Our data demonstrate the utility of this new cell line in high-throughput drug/chemical screens to identify potential therapeutic agents. The NPC

A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease

Background Lysosomal storage disorders (LSDs), are a heterogeneous group of rare disorders caused by defects in genes encoding for proteins involved in the lysosomal degradation of macromolecules. They occur at a frequency of about 1 in 5,000 live births, though recent neonatal screening suggests a higher incidence. New treatment options for LSDs demand a rapid, early diagnosis of LSDs if maximal clinical benefit is to be achieved. Methods Here, we describe a novel, highly specific and sensitive biomarker for Niemann-Pick Type C disease type 1 (NPC1), lyso-sphingomyelin-509. We cross-validate this biomarker with cholestane-3β,5α,6β-triol and relative lysosomal volume. The primary cohort for establishment of the biomarker contained 135 NPC1 patients, 66 NPC1 carriers, 241 patients with other LSDs and 46 healthy controls. Results With a sensitivity of 100.0% and specificity of 91.0% a cut-off of 1.4 ng/ml was established. Comparison with cholestane-3β,5α,6β-triol and relative acidic compartment volume measurements were carried out with a subset of 125 subjects. Both cholestane-3β,5α,6β-triol and lyso-Sphingomyelin-509 were sufficient in establishing the diagnosis of NPC1 and correlated with disease severity. Conclusion In summary, we have established a new biomarker for the diagnosis of NPC1, and further studies will be conducted to assess correlation to disease progress and monitoring treatment

A phase 1/2 open label nonrandomized clinical trial of intravenous 2-hydroxypropyl-β-cyclodextrin for acute liver disease in infants with Niemann-Pick C1

Introduction: Niemann-Pick C (NPC) is an autosomal recessive disease due to defective NPC1 or NPC2 proteins resulting in Methods: Infants received intravenous 2HPBCD twice a week for 6 weeks, followed by monthly infusion for 6-months. Primary outcome measure was reduction of plasma (3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), a bile acid generated from cholesterol sequestered in lysosome. Results: Three participants completed this protocol. A fourth patient received intravenous 2HPBCD under an emergency investigational new drug study but later expired from her underlying condition. The three protocol patients are living and have improved liver enzymes and TCG. No patient has experienced a drug-related adverse event. Conclusion: Intravenous 2HPBCD was tolerated in three infants with liver disease due to NPC

Access to shops: The views of low-income shoppers

Concern is mounting as the retail stranglehold upon access to food grows. Research on the implications of restructuring retailing and health inequality has failed to involve low-income consumers in this debate. This paper reports on an exercise conducted for the UK Government's, Social Exclusion Unit's Policy Action Team on Access to Shops. The survey provides a useful baseline of the views of low-income groups in England. The choices that people on low income can make were found to be dominated by certain factors such as income and, most importantly, transport. Consumers reported varying levels of satisfaction with retail provision. The findings suggest gaps between what people have, what they want and what the planning process does and does not offer them. Better policy and processes are needed to include and represent the interests of low-income groups

Extreme infrared variables from UKIDSS-I. A concentration in star-forming regions

We present initial results of the first panoramic search for high-amplitude near-infrared variability in theGalactic plane.We analyse the widely separated two-epoch K-band photometry in the fifth and seventh data releases of the UKIDSS Galactic plane survey.We find 45 stars with δK > 1 mag, including two previously known OH/IR stars and a Nova. Even though the midplane is not yet included in the data set, we find the majority (66 per cent) of our sample to be within known star-forming regions (SFRs), with two large concentrations in the Serpens OB2 association (11 stars) and the Cygnus-X complex (12 stars). Sources in SFRs show spectral energy distributions that support classification as young stellar objects (YSOs). This indicates that YSOs dominate the Galactic population of high-amplitude infrared variable stars at low luminosities and therefore likely dominate the total high-amplitude population. Spectroscopic follow up of the DR5 sample shows at least four stars with clear characteristics of eruptive premain- sequence variables, two of which are deeply embedded. Our results support the recent concept of eruptive variability comprising a continuum of outburst events with different timescales and luminosities, but triggered by a similar physical mechanism involving unsteady accretion. Also, we find what appears to be one of the most variable classical Be stars. © 2014 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society

On Solving the Coronal Heating Problem

This article assesses the current state of understanding of coronal heating, outlines the key elements of a comprehensive strategy for solving the problem, and warns of obstacles that must be overcome along the way.Comment: Accepted by Solar Physics; Published by Solar Physic